GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 245Gene Ther Mol Biol Vol 7, 245-254, 2003Protective effect of heat shock proteins:potential for gene therapyReview ArticleDavid S. LatchmanInstitute of Child Health, 30 Guilford Street, London WC1N 1EH & Birkbeck, University of London Malet Street, LondonWC1E 7HX__________________________________________________________________________________*Correspondence: David S. Latchman, Tel (+44) 20 7631 6274; Fax (+44) 20 7631 6259; e-mail: d.latchman@bbk.ac.ukKey words: heat shock proteins (hsps); Drosophila protein, gene therapyAbbreviations: heat shock proteins, (hsps); herpes simplex virus, (HSV); heat shock transcription factor, (HSF-1); cytokinecardiotrophin-1, (CT-1)Received: 24 September 2003; Accepted: 30 September 2003; electronically published: December 2003Contributed by Dr. LatchmanSummaryThe heat shock proteins (hsps) are expressed in normal cells but their expression is enhanced by a number ofdifferent stresses including heat and ischaemia. They play important roles in chaperoning the folding of otherproteins and in protein degradation. In the heart and the brain, a number of studies have shown that priorinduction of the hsps by a mild stress has a protective effect against a more severe stress. Moreover, over-expressionof an individual hsp in cardiac or neuronal cells in culture and in the intact heart or brain of either transgenicanimals or using virus vectors, also produces a protective effect, directly demonstrating the ability of the hsps toproduce protection. These findings indicate the potential importance of developing procedures for elevating hspexpression in a safe and efficient manner in human individuals using either pharmacological or gene therapyprocedures.I. IntroductionHeat shock proteinsIt is now over forty years since Ritossa observed thatexposure of the larval salary gland of Drosophila toelevated temperature resulted in the appearance of newpuffs in the giant chromosomes of these cells (Ritossa,1962). It is now clear that these puffs represent thetranscriptional induction of specific genes which encode agroup of proteins known as the heat shock proteins (forreview see Lindquist and Craig, 1988; Parsell andLindquist, 1993).Although originally demonstrated in Drosophila, theinduction of a small number of heat shock proteins byelevated temperature, is observed in all organisms studiedranging from prokaryotic bacteria to mammals includingman. Moreover, this evolutionary conservation extends notonly to the existence of the heat shock response indifferent organisms but also to the induced proteinsthemselves which are very similar to one another in verydifferent organisms. Thus, the best characterised hsps,hsp90, hsp70, hsp65 and hsp27 (each hsp is namedaccording to its mass in kilodaltons) are induced inresponse to heat in all organisms studied from bacteria toman and are highly conserved between different species,for example, the hsp90 protein from mammals shows 60%amino acid identity with the corresponding yeast proteinand 78% with the Drosophila protein (Rebbe et al, 1987).The various hsps and their characteristics are listed inTable 1.Although originally identified on the basis of theirinduction by elevated temperature and therefore named theheat shock proteins, these proteins are in fact induced by awide range of stimuli which are potentially damaging tothe cell. Such inducers include infections with a widevariety of different viruses (Collins and Hightower, 1982;Khandijan and Turler, 1983; La Thangue and Latchman,1988), treatment with ethanol (Plesset et al, 1982), steroidhormones (Norton and Latchman, 1989), and amino acidanalogues (Li and Laszlo, 1985). Interestingly, hsps arealso induced by processes which may occur during humandisease, notably exposure of specific cells such as cardiacor neuronal cells to ischaemia or elevated levels of freeradicals (Nowak, 1985; Polla, 1988).The strong evolutionary conservation of the hsps orstress proteins which was discussed above and theirinduction by a variety of stressful stimuli, indicates thatthey are likely to have some critical function in the cellular245